Myocardial infarction (MI), commonly known as heart attack, is associated with modifiable risk factors but nonetheless remains a leading cause of death and severe disability worldwide. (Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with MI in 52 countries (the INTERHEART study): case-control study. Lancet. 364:937-52 (2004)). Toward prevention, contemporary American and European guidelines recommend an integrated two-step approach in which risk assessment (prediction) is followed by individualized risk reduction (therapy), if needed; the higher the risk, the more aggressive the prescribed preventive care. (Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143-421 (2002); European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Eur. Heart J. 28:2375-414 (2007)).
Risk assessment in primary prevention of MI has not changed dramatically in the last 40 years. It remains based upon the risk factor concept introduced by the Framingham Heart Study in the 1960's. (Kannel W B, Dawber T R, Kagan A, Revotskie N, Stokes J, 3rd. Factors of risk in the development of coronary heart disease—six year follow-up experience. The Framingham Study. Ann. Intern. Med. 55:33-50 (1961)). Because individual risk factors such as plasma cholesterol and blood pressure have low independent predictive ability (Ware J H. The limitations of risk factors as prognostic tools. N. Engl. J. Med. 355:2615-7 (2006)), they have been combined to generate global risk assessment measures such as the Framingham Risk Score (FRS) and the European SCORE (Systematic Coronary Risk Evaluation). (Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143-421 (2002); European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Eur. Heart J. 28:2375-414 (2007)).
These multivariable risk prediction models provide estimates of 10-year absolute risk and relative risk. The absolute risk is used primarily to assess the need for pharmacological risk reduction, whereas the relative risk is more useful in identifying younger individuals for lifestyle modification to reduce their otherwise high lifetime risk.
Although this two-step preventive approach is sound, it is far from perfect in its present form because established risk factors have limited predictive power even when combined (Wald N J, Morris J K, Rish S. The efficacy of combining several risk factors as a screening test. J. Med. Screen. 12:197-201 (2005)), and progression of subclinical disease to clinical MI events still occurs despite initiation of the recommended “optimal” therapy. (Koenig W. Treating residual cardiovascular risk: will lipoprotein-associated phospholipase A2 inhibition live up to its promise? J. Am. Coll. Cardiol. 51:1642-4 (2008)). Most MI events occur in individuals classified in FRS/SCORE low and intermediate risk categories, i.e., among misclassified individuals. Further, a substantial residual risk persists even with the best available medical therapy. (Koenig W. Treating residual cardiovascular risk: will lipoprotein-associated phospholipase A2 inhibition live up to its promise? J. Am. Coll. Cardiol. 51:1642-4 (2008); Naghavi M, Falk E, Hecht H S, et al. From vulnerable plaque to vulnerable patient—Part III: Executive summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force report. Am. J. Cardiol. 98:2 H-15H (2006); Lauer M S. Primary prevention of atherosclerotic cardiovascular disease: the high public burden of low individual risk. JAMA. 297:1376-8 (2007)).
Thus, there is a need to improve both the detection and the treatment of individuals at highest risk for a MI event.